This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project evaluates the pathophysiology of abnormal motor symptoms developed in the evolution of Parkinson's disease (PD). Dopamine replacement has beneficial effects in the early stages, but long-term therapy often fails to completely restore normal mobility, and may even produce additional motor abnormalities. Altered dopamine responses have been related to changes in dopamine receptor-mediated mechanisms regulating the activity of striatal neurons. However, changes in other neurotransmitter systems may also play a role. Based on our previous studies in this project, we focus our continuation studies on the role of striatal glutamatergic transmission in the pathophysiology of abnormal responses to levodopa. The goal of these studies is to identify pharmacologic targets that could serve to develop new treatments for the long-term therapy of PD. The project comprises four aims: (1) To study the relationship between glutamatergic hyperactivity and altered discharges of striatal medium spiny neurons (MSNs) in parkinsonian monkeys. Electrophysiologic recordings of MSNs are combined with striatal injections of specific glutamate receptor antagonists. (2) To examine whether increased glutamate release is involved in the altered MSN discharges. We will reduce glutamatergic levels with cannabinoid CB1-acting drugs infused into the putamen of parkinsonian monkeys to study MSN firing changes and levodopa motor responses. (3) To study the changes in indirect striatal outputs that develop in chronic PD and are associated with abnormal responses to dopaminergic drugs. We will use glutamate antagonists in putaminal infusions and record the neuronal activity of the external segment of the globus pallidus in normal and parkinsonian monkeys.